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Three-dimensional pharmacophore design and biochemical screening identifies substituted 1,2,4-triazoles as inhibitors of the annexin A2-S100A10 protein interaction

Reddy, Tummala R.K.; Li, Chan; Fischer, Peter M.; Dekker, Lodewijk V.

Authors

Tummala R.K. Reddy

Chan Li

Peter M. Fischer

Lodewijk V. Dekker

Abstract

Protein interactions are increasingly appreciated as targets in small-molecule drug discovery. The interaction between the adapter protein S100A10 and its binding partner annexin A2 is a potentially important drug target. To obtain small-molecule starting points for inhibitors of this interaction, a three-dimensional pharmacophore model was constructed from the X-ray crystal structure of the complex between S100A10 and annexin A2. The pharmacophore model represents the favourable hydrophobic and hydrogen bond interactions between the two partners, as well as spatial and receptor site constraints (excluded volume spheres). Using this pharmacophore model, UNITY flex searches were carried out on a 3D library of 0.7 million commercially available compounds. This resulted in 568 hit compounds. Subsequently, GOLD docking studies were performed on these hits, and a set of 190 compounds were purchased and tested biochemically for inhibition of the protein interaction. Three compounds of similar chemical structure were identified as genuine inhibitors of the binding of annexin A2 to S100A10. The binding modes predicted by GOLD were in good agreement with their UNITY-generated conformations. We synthesised a series of analogues revealing areas critical for binding. Thus computational predictions and biochemical screening can be used successfully to derive novel chemical classes of protein–protein interaction blockers.

Journal Article Type Article
Publication Date May 29, 2012
Journal ChemMedChem
Print ISSN 1860-7179
Electronic ISSN 1860-7179
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 7
Issue 8
Institution Citation Reddy, T. R., Li, C., Fischer, P. M., & Dekker, L. V. (2012). Three-dimensional pharmacophore design and biochemical screening identifies substituted 1,2,4-triazoles as inhibitors of the annexin A2-S100A10 protein interaction. ChemMedChem, 7(8), doi:10.1002/cmdc.201200107
DOI https://doi.org/10.1002/cmdc.201200107
Publisher URL http://pubmedcentralcanada.ca/pmcc/articles/PMC3505905/
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0




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